Multi-stage calcination method for making hollow silica spheres

ABSTRACT

A method for forming hollow silica spheres by dissolving a hydrolyzable aryl silane in an aqueous solution of water and an acid to form a hydrolyzed silane solution, mixing the hydrolyzed silane solution with a hydroxide base to form a precipitate, and calcining the precipitate in a multi-stage calcination procedure that includes (a) heating to a first temperature of 180 to 240° C. with a first ramp rate of 3 to 10° C./min and holding the first temperature for 2 minutes to 2 hours, then (b) heating to a second temperature of 600 to 740° C. at a second ramp rate of 0.1 to 4° C./min, and holding the second temperature for 2 to 24 hours.

BACKGROUND OF THE DISCLOSURE Technical Field

The present disclosure relates to a method of making hollow silicaspheres. In particular, methods of making hollow silica spheres using ahydrolyzable aryl silane and a multi-stage calcination procedure.

Description of the Related Art

The “background” description provided herein is for the purpose ofgenerally presenting the context of the disclosure. Work of thepresently named inventors, to the extent it is described in thisbackground section, as well as aspects of the description which may nototherwise qualify as prior art at the time of filing, are neitherexpressly or impliedly admitted as prior art against the presentdisclosure.

In the recent years, hollow silica spheres (HSS) have emerged as aversatile material for many industrial, medical and scientificapplications. Nanotechnology and nanoscience have been focusing onhollow particles with nanometer to micrometer dimensions. Metal basedhollow nanostructures have received increasing attention because oftheir specific plasmonic properties [S. J. Oldenburg, R. D. Averitt, S.L. Westcott and N. J. Halas, Chem Phys Lett, 1998, 288,243-247—incorporated herein by reference in its entirety], and catalyticactivities [S. W. Kim, M. Kim, W. Y. Lee and T. Hyeon, J Am Chem Soc,2002, 124, 7642-7643—incorporated herein by reference in its entirety]which are completely distinct from their solid counterparts. Forinstance, gold nanoshells have been applied for contrast enrichment inoptical imaging and photothermal initiation in drug release applications[S. J. Oldenburg, J. B. Jackson, S. L. Westcott and N. J. Halas, ApplPhys Lett, 1999, 75, 2897-2899; S. R. Sershen, S. L. Westcott, N. J.Halas and J. L. West, J Biomed Mater Res, 2000, 51, 293-298; J. L. Westand N. J. Halas, Curr Opin Biotech, 2000, 11, 215-217—each incorporatedherein by reference in its entirety].

Hollow particles tend to have beneficial optical activities, thermalinsulation, and low density and have been widely used in drug delivery[S. J. Oldenburg, R. D. Averitt, S. L. Westcott and N. J. Halas, ChemPhys Lett, 1998, 288, 243-247; S. W. Kim, M. Kim, W. Y. Lee and T.Hyeon, J Am Chem Soc, 2002, 124, 7642-7643—each incorporated herein byreference in its entirety], plasmonic applications [S. J. Oldenburg, R.D. Averitt, S. L. Westcott and N. J. Halas, Chem Phys Lett, 1998, 288,243-247—incorporated herein by reference in its entirety], catalysis [S.W. Kim, M. Kim, W. Y. Lee and T. Hyeon, J Am Chem Soc, 2002, 124,7642-7643—incorporated herein by reference in its entirety],bioencapsulation [S. M. Marinakos, M. F. Anderson, J. A. Ryan, L. D.Martin and D. L. Feldheim, J Phys Chem B, 2001, 105, 8872-8876; S. M.Marinakos, J. P. Novak, L. C. Brousseau, A. B. House, E. M. Edeki, J. C.Feldhaus and D. L. Feldheim, J Am Chem Soc, 1999, 121, 8518-8522—eachincorporated herein by reference in its entirety], medical diagnostics[P. Tartaj, M. D. Morales, S. Veintemillas-Verdaguer, T.Gonzalez-Carreno and C. J. Serna, J Phys D Appl Phys, 2003, 36,R182-R197—incorporated herein by reference in its entirety], structuralmaterials, and composite electronic materials [J. K. Cochran, Curr OpinSolid St M, 1998, 3, 474-479, M. Ohmori and E. Matijevic, J ColloidInterf Sci, 1992, 150, 594-598—incorporated herein by reference in itsentirety].

Hollow silica particles are typically prepared by coating/depositing asilicon-containing material on the surface of a template, and thenremoving the used template, leaving behind only the silicon-containingmaterial. This kind of template method generally employs organicspheres, inorganic particles, or metal crystals as the template [P. V.Braun and S. I. Stupp, Materials Research Bulletin, 1999, 34, 463-469;P. J. Bruinsma, A. Y. Kim, J. Liu and S. Baskaran, Chem Mater, 1997, 9,2507-2512; F. Caruso, X. Shi, R. A. Caruso and A. Susha, AdvancedMaterials, 2001, 13, 740-744; D. H. W. Hubert, M. Jung and A. L. German,Advanced Materials, 2000, 12, 1291-1294; M. Jafelicci Jr, M. RosalyDavolos, F. Jose dos Santos and S. Jose de Andrade, Journal ofNon-Crystalline Solids, 1999, 247, 98-102; H. T. Schmidt and A. E.Ostafin, Advanced Materials, 2002, 14, 532-535; L. Wang, T. Sasaki, Y.Ebina, K. Kurashima and M. Watanabe, Chem Mater, 2002, 14,4827-4832—each incorporated herein by reference in its entirety].However, such template methods, commonly called “scarified templatemethods”, require template removal after the coating process [T. Ung, L.M. Liz-Marzán and P. Mulvaney, Langmuir, 1998, 14, 3740-3748; Y. Yin, Y.Lu, B. Gates and Y. Xia, Chem Mater, 2001, 13, 1146-1148—eachincorporated herein by reference in its entirety]. This can be both timeconsuming and wasteful, as the template is merely sacrificial and is notincorporated into the final product.

Recent efforts have been made to prepare hollow particles withouttemplates, by using self-template methods or device-based approaches(called “nozzle based method”) in order to avoid template waste. Whilesuch methods generally simplify the procedures for making hollowparticles, they have not yielded satisfactory results.

In view of the forgoing, one object of the present disclosure is toprovide methods for forming hollow silica spheres using multi-stagecalcining procedures that eliminates the need for templates and formsrobust hollow silica spheres with properties that enable their use in awide variety of applications.

BRIEF SUMMARY OF THE DISCLOSURE

Accordingly, it is one object of the present invention to provide novelmethods of forming hollow silica spheres using calcining procedures thateliminates the need for templates.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by employing hydrolyzable arylsilanes and multi-stage calcining procedures for the production ofhollow silica spheres having desirable monodispersity, uniformity,degrees of hollowness, mechanical properties, aqueous solubility, andsurface characteristics.

Therefore, according to a first aspect, the present disclosure relatesto a method for forming hollow silica spheres that involves (i)dissolving a hydrolyzable aryl silane in an aqueous solution comprisingwater and an acid to form a hydrolyzed silane solution, (ii) mixing thehydrolyzed silane solution with a hydroxide base to form a precipitate,and (iii) calcining the precipitate to form the hollow silica spheres,wherein the calcining is performed by (iiia) heating to a firsttemperature of 180 to 240° C. with a first ramp rate of 3 to 10° C./minand holding the first temperature for 2 minutes to 2 hours, then (iiib)heating to a second temperature of 600 to 740° C. at a second ramp rateof 0.1 to 4° C./min, and holding the second temperature for 2 to 24hours.

In some embodiments, the hydrolyzable aryl silane is a trialkoxy(aryl)silane.

In some embodiments, the hydrolyzable aryl silane is trimethoxy(phenyl)silane.

In some embodiments, the acid is nitric acid.

In some embodiments, the hydroxide base is ammonium hydroxide.

In some embodiments, the first temperature is 195 to 210° C.

In some embodiments, the first ramp rate is 4 to 6° C./min

In some embodiments, the first temperature is held for 15 to 45 minutes.

In some embodiments, the second temperature is 650 to 670° C.

In some embodiments, the second ramp rate is of 1 to 2° C./min.

In some embodiments, the second temperature is held for 12 to 20 hours.

In some embodiments, a template is not employed for forming the hollowsilica spheres.

In some embodiments, the hollow silica spheres comprise asilica-containing shell surrounding a core, wherein thesilica-containing shell has a higher density of silica compared to thecore.

In some embodiments, the hollow silica spheres have an average degree ofhollowness, defined as a maximum peak intensity of the core divided by aminimum peak intensity of the silica-containing shell, each measuredwith transmission electron microscopy, of 3 to 8.

In some embodiments, the silica-containing shell has a thickness ofabout 150 to 210 nm, and the core has a diameter of about 100 to 230 nm.

In some embodiments, the hollow silica spheres have an average diameterof 500 to 530 nm.

In some embodiments, the hollow silica spheres are monodisperse with acoefficient of variation, defined as a ratio of the standard deviationto the mean diameter of the hollow silica spheres, of less than 5%.

In some embodiments, the hollow silica spheres have a solubility inwater of 0.1 to 50 mg per 10 mL of water.

In some embodiments, the hollow silica spheres have a specific surfacearea of 350 to 450 m²/g.

In some embodiments, the hollow silica spheres have a t-plot externalsurface area of 40 to 75 m²/g.

In some embodiments, the hollow silica spheres have an average porediameter of 1.7 to 8 nm with a cumulative pore volume of 0.02 to 0.035cm³/g.

The foregoing paragraphs have been provided by way of generalintroduction, and are not intended to limit the scope of the followingclaims. The described embodiments, together with further advantages,will be best understood by reference to the following detaileddescription taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the disclosure and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 is a schematic illustration of method used to synthesize,biocompatible HSS.

FIG. 2 is an SEM micrograph of HSS after calcination.

FIG. 3A is a TEM image of HSS spheres before calcination.

FIG. 3B is an intesity profile taken from the area shown by the lineFIG. 3A.

FIG. 3C is a TEM image of HSS spheres after calcination.

FIG. 3D is an intesity profile taken from the area shown by the lineFIG. 3A.

FIG. 4A shows an FTIR spectrum of non-calcined hollow silica particles.

FIG. 4B shows an FTIR spectrum of calcined hollow silica particles.

FIG. 4C shows a TGA analysis of non-calcined and calcined HSS samples.

FIG. 5 shows results from a solubility test where the calcined HSS wassoluble in water while non-calcined silica particles were hydrophobic innature, and not soluble in water where they can be seen on the surfaceof the water.

FIGS. 6A-6D shows TEM images of silica particles produced using asingle-stage calcination procedure involving heating to to 600° C. witha heating rate of 10° C./min.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Embodiments of the present disclosure will now be described more fullyhereinafter with reference to the accompanying drawings, in which some,but not all of the embodiments of the disclosure are shown.

As used herein, the words “a” and “an” and the like carry the meaning of“one or more”. Additionally, within the description of this disclosure,where a numerical limit or range is stated, the endpoints are includedunless stated otherwise. Also, all values and subranges within anumerical limit or range are specifically included as if explicitlywritten out.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event(s) can or cannot occur or the subsequentlydescribed component(s) may or may not be present (e.g. 0 wt. %).

The term “comprising” is considered an open-ended term synonymous withterms such as including, containing or having and is used herein todescribe aspects of the invention which may include additional steps,components, functionality and/or structure. Terms such as “consistingessentially of” are used to identify aspects of the invention whichexclude particular steps, components, functionality and/or structurethat are not explicitly recited in the claim but would otherwise have amaterial effect on the basic and novel properties of the hollow silicaspheres. The term “consisting of” describes aspects of the invention inwhich only those steps or features explicitly recited in the claims areincluded and thus other steps or components not explicitly or inherentlyincluded in the claim are excluded.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included. For example, if a particular elementor component in a composition is said to have 8 wt. %, it is understoodthat this percentage is in relation to a total compositional percentageof 100%, unless stated otherwise.

In regard to calcination temperatures and procedures, the term “ramp” or“ramping” refers to a nonisothermal state where the temperature isvaried in a particular direction (e.g., increased or decreased) overtime, the purpose of which is to move from one temperature setting toanother. On the other hand, the terms “held” or “holding” herein referto an isothermal state where the referenced temperature (e.g., the firsttemperature or the second temperature) is maintained at a constant ornear constant value (i.e., plus or minus 5° C., preferably plus or minus4° C., preferably plus or minus 3° C., preferably plus or minus 2° C.,preferably plus or minus 1° C.) for a certain period of time. Forexample, when the first temperature is selected to be 200° C., holdingthis first temperature for 25 to 35 minutes means that the temperatureis maintained at 200° C. plus/minus 5° C. for a 25 to 35 minute timeperiod before the temperature is subsequently changed. Therefore, theterms “held” or “holding” distinguish from nonisothermal states (i.e.,during periods of temperature ramping) where the temperature is beingraised or lowered at a particular ramping rate range. Again using theabove example, when the temperature is being ramped from 150° C. to atarget temperature of 250° C. over a certain time period, this scenariowould not constitute a “hold” in temperature even though 200° C. may betransiently achieved in moving from 150° C. up to 250° C.

When referencing hollow silica spheres, “hollow” refers to a centralarea (i.e., a core portion) of a particle which has a lower density ofsilica compared to the surrounding structure (i.e., the shell portion).While the definition of “hollow” may encompass a continuous void that iscompletely free of silica, this is not a requirement, and some silicamay be disposed within the core portion. By way of example, a silicaparticle which has a substantially continuous density of silica from onepoint on the particle though the center of the particle to a pointdirectly across from it would be considered solid herein and not hollow,whereas a silica particle that has 60-80 wt. % of a total silica contentlocated in the shell portion, with the remaining 20-40 wt. % of a totalsilica content located in the central area would be considered hollowherein.

Methods

According to a first aspect, the present disclosure relates to a methodfor forming hollow silica spheres (HSS), which first involves mixingand/or dissolving a hydrolyzable aryl silane in an aqueous solutioncomprising water and an acid to form a hydrolyzed silane solution.

The hydrolyzable aryl silane employed may be any silane having at leastone aryl substituent and at least one hydrolyzable group bonded directlyto the Si atom. Hydrolyzable groups include, but are not limited to,alkoxy groups (e.g., methoxy, ethoxy, propoxy, iso-propoxy, t-butoxy, aswell as substituted variants, as well as mixtures of one or more ofthese groups) and halo groups (e.g., chloro, bromo, iodo, and fluoro),including mixtures of alkoxy and halo groups. The hydrolyzable arylsilane may therefore have one, two, or three hydrolyzable groups,preferably three hydrolyzable groups which may be the same or different,most preferably the same.

Likewise, the hydrolyzable aryl silane employed may have one, two, orthree aryl groups, preferably one aryl group. In cases where thehydrolyzable aryl silane contains one aryl group, the hydrolyzable arylsilane may optionally include one or two alkyl or vinyl substituentsbonded directly to the Si atom. The term “aryl”, as used herein, andunless otherwise specified, refers to an aromatic group containingcarbon in the aromatic ring(s), such as phenyl, biphenyl, naphthyl,anthracenyl, and the like, as well as optionally substituted analogsthereof. The term aryl is also meant to include “heteroaryl” groups, oraryl substituents where at least one carbon atom is replaced with aheteroatom (e.g. nitrogen, oxygen, sulfur) so long as the heteroatom isnon-nucleophilic so as to prevent reaction with the hydrolyzable groupof a neighboring hydrolyzable aryl silane. Such heteroaryl groups mayinclude, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl,quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thia-diazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, benzodioxane, and the like, as well as optionallysubstituted analogs thereof. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2) oroptionally protected with protecting groups as necessary as known tothose skilled in the art, for example, as taught in Greene, et al.,“Protective Groups in Organic Synthesis”, John Wiley and Sons, SecondEdition, 1991, hereby incorporated by reference in its entirety. Theterm “substituted” refers to at least one hydrogen atom that is replacedwith a non-hydrogen group, provided that normal valencies are maintainedand that the substitution results in a stable compound. When a compoundis noted as “optionally substituted”, the substituents are selected fromthe exemplary group including, but not limited to, alkyl, cycloalkyl,cycloalkylalkyl, arylalkyl, heteroaryl, aryl, heterocyclyl, alkoxy,cycloalkyloxy, aryloxy, arylalkyloxy, aroyl, alkanoyl, alkanoyloxy,carboxy, alkoxycarbonyl, halo (e.g. chlorine, bromine, fluorine oriodine), dialkylamino, diarylamino, arylalkylamino, alkanoylamino,nitro, cyano, carbamyl, alkylthio, arylthio, arylalkylthio,alkylsulfonyl (i.e. —SO₂alkyl), arylsulfonyl (i.e. —SO₂aryl),arylalkylsulfonyl (i.e. —SO₂arylalkyl), haloalkyl, oxo, and the like.

Exemplary hydrolyzable aryl silanes include, but are not limited to,ethoxy(diphenyl)vinyl silane, trichloro[4-(chloromethyl)phenyl] silane,dimethoxy(diphenyl) silane, diethoxy(diphenyl) silane,diethoxy(methyl)phenyl silane, trichloro(phenyl) silane,triethoxy(phenyl) silane, and trimethoxy(phenyl) silane.

In preferred embodiments, the hydrolyzable aryl silane is atrialkoxy(aryl) silane, more preferably a trialkoxy(phenyl) silane, mostpreferably trimethoxy(phenyl) silane.

It is also envisioned that hydrolyzable arylalkyl silanes may be used inaddition to, or in lieu of the hydrolyzable aryl silane, whereby thearyl group is present but is bonded to the Si atom through an alkylenelinking group. For example, trimethoxy(2-phenylethyl) silane may beused.

In preferred embodiments, the hydrolyzable aryl silane is the onlysource, reagent, or starting material used in the present disclosure tosynthesize the hollow silica spheres that contains aryl functionality.In preferred embodiments, the hydrolyzable aryl silane is the only Sisource utilized in the present method, and other sources of Si, forexample tetraethyl orthosilicate (TEOS), may be optionally excluded.

Hydrolysis may be carried out by dissolving the hydrolyzable aryl silanein the aqueous solution comprising, consisting essentially of, orconsisting of water and an acid with optional stirring and/or heating,for example, heating to a temperature of 30-100° C., preferably 40-90°C., preferably 50-80° C., preferably 55-65° C., preferably 60° C. Theamount of the hydrolyzable aryl silane dissolved in the aqueous solutionmay be varied, although typically a volume ratio of the hydrolyzablearyl silane to the volume of the aqueous solution ranges from 1:50 to1:100, preferably 1:60 to 1:95, preferably 1:70 to 1:90, preferably 1:75to 1:85. The water may be tap water, distilled water, twice distilledwater, deionized water, deionized distilled water, reverse osmosiswater, or various other water sources.

The acid employed in the hydrolysis reaction is preferably a mineralacid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuricacid, hydrobromic acid, perchloric acid, and hydroiodic acid. Inpreferred embodiments, the acid is nitric acid. A concentration of theacid in the aqueous solution may vary widely, but typical concentrationsrange from 1-15 mM, preferably 2-13 mM, preferably 3-11 mM, preferably4-10 mM, preferably 5-9 mM, preferably 6-8 mM.

After combining the hydrolyzable aryl silane with the aqueous solution,the hydrolysis reaction is allowed to take place for an appropriate timeto convert the hydrolyzable aryl silane into a partially or fullyhydrolyzed form, whereby the hydrolyzable group (e.g., methoxy, chloro,etc.) is replaced by —OH, to form a hydrolyzed silane solution. In mostcases, especially when heating is employed, less than 10 minutes,preferably less than 5 minutes, more preferably less than 3 minutes isenough to result in complete hydrolysis, although longer hydrolysistimes may also be employed.

Once hydrolysis is deemed sufficiently complete, the hydrolyzed silanesolution may be mixed with an appropriate hydroxide base to condense thehydrolyzed silane thereby forming a precipitate. The hydroxide baseemployed in the condensation reaction may be an alkali metal hydroxide(e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide,rubidium hydroxide, and cesium hydroxide), an alkali earth metalhydroxide (e.g., magnesium hydroxide, calcium hydroxide, strontiumhydroxide, and barium hydroxide), or an ammonium hydroxide (e.g.,ammonium hydroxide, tetramethylammonium hydroxide, triethylammoniumhydroxide, trimethylanilinium hydroxide, etc.). In preferredembodiments, the hydroxide base is ammonium hydroxide.

The hydroxide base may be used in the form of a solid such as a powder,beads or pellets, or may be used in the form of an aqueous basesolution. When used as a solid, the hydroxide base is preferably in theform of beads or pellets, more preferably in the form of beads, andstill more preferably in the form of beads having an average beaddiameter of about 0.1 to 2 mm, preferably about 0.2 to 1.5 mm, morepreferably about 0.5 to 1 mm. When the hydroxide base is used in theform of an aqueous base solution, the concentration thereof ispreferably about 10 to 50%, preferably about 20 to 40%, more preferablyabout 30 to 35%, most preferably about 33%, by weight of hydroxide baseper total volume of the aqueous base solution.

In some embodiments, an excess of hydroxide base is combined with thehydrolyzed silane solution. For example, a molar ratio of hydroxide baseemployed in the condensation reaction to the acid employed in thehydrolysis reaction may be about 100:1 to 1000:1, preferably 200:1 to900:1, preferably 300:1 to 800:1, preferably 400:1 to 700:1, preferablyabout 500:1. Upon addition of the hydroxide base, a precipitategenerally forms immediately at ambient temperatures (i.e., 20-25° C.),or alternatively upon optional heating to 30-80° C., or 40-70° C., or50-60° C. The resulting suspension may be allowed to settle, oralternatively may be stirred, for example with a mechanical or magneticstirrer.

The precipitate may then be separated from the suspension, for exampleby filtration, centrifugation, decantation, and the like, and optionallywashed with an organic solvent, water, or both. Exemplary organicsolvents may include, but are not limited to C₁ to C₄ lower alkanols,for example, methanol, ethanol, isopropanol, butanol; polyols and polyolethers, for example, glycol, 1,3-propanediol, 1,3-butanediol,2-butoxyethanol, propylene glycol, diethylene glycol, ethylene glycolmonomethyl ether, and propylene glycol monomethyl ether. Afterwards, theprecipitate may then be dried at a temperature of 20-150° C., preferably50-120° C., preferably 60-100° C., preferably 80-90° C. under standardpressure or under vacuum. For examples of similarhydrolysis/condensation procedures, see [B. P. M. Marini, F. Pilati, andP. Fabbri, Colloids Surf., 2008, A 317, (1-3); Y. Taniguchi, K. Shirai,H. Saitoh, T. Yamauchi and N. Tsubokawa, Polymer, 2005, 46,2541-2547—each incorporated herein by reference in its entirety].

The method may next involve calcining the precipitate using amulti-stage calcining procedure, preferably a two-stage calciningprocedure, to form the hollow silica spheres with advantageousproperties as will be discussed hereinafter. In some embodiments, thecalcination step is performed in a furnace using, for example, a pre-settemperature program discussed below, or using other variable temperaturesystems known by those of ordinary skill in the art.

In a first stage of the calcining process, the precipitate may be heatedto a first temperature of 180 to 240° C., preferably 185 to 230° C.,preferably 190 to 220° C., preferably 195 to 210° C., preferably about200° C., with a first ramp rate of 3 to 10° C./min, preferably 3.4 to 9°C./min, preferably 3.6 to 8° C./min, preferably 3.8 to 7° C./min,preferably 4 to 6° C./min, most preferably about 5° C./min. Once thefirst temperature is reached, the first temperature may be held for 2minutes to 2 hours, preferably from 10 minutes to 1.5 hours, preferablyfrom 12 minutes to 1 hour, preferably from 14 to 55 minutes, preferablyfrom 15 to 45 minutes, preferably from 20 to 40 minutes, preferably from25 to 35 minutes, preferably about 30 minutes.

After holding the first temperature, the second stage of the calciningprocess may involve heating to a second temperature of 600 to 740° C.,preferably 610 to 730° C., preferably 620 to 720° C., preferably 630 to700° C., preferably 640 to 680° C., preferably 650 to 670° C.,preferably about 660° C., with a second ramp rate of 0.1 to 4° C./min,preferably 0.3 to 3.5° C./min, preferably 0.5 to 3° C./min, preferably0.8 to 2.5° C./min, preferably 1 to 2° C./min, most preferably about1.5° C./min. Once the second temperature is reached, the secondtemperature may be held for 2 to 24 hours, preferably 4 to 23 hours,preferably 6 to 22 hours, preferably 8 to 21 hours, preferably 12 to 20hours, preferably 14 to 18 hours, preferably 15 to 17 hours, mostpreferably about 16 hours to form the hollow silica spheres of thepresent disclosure.

In some embodiments, other stages may be incorporated into themulti-stage calcining program. For example a third stage may be added inbetween the first and the second stage that holds on a third temperaturewhich is between the first and second temperatures (i.e., anintermediate stage). Likewise, a fourth stage may be added after thesecond stage to hold at a fourth temperature that is higher than that ofthe second temperature to finish the calcining program (i.e., afinishing stage). Various other stages may also be included, as well asother variations known for calcination processes, such as changes ofgaseous atmosphere may be practiced.

As will become clear, the methods disclosed herein provide hollow silicaspheres having unexpected and superior monodispersity, uniformity,degree of hollowness, mechanical properties, aqueous solubility, andsurface characteristics compared to those produced without calcinationand those produced using a single-stage calcination program.

Further, the methods described herein do not require the use of atemplate for forming the hollow spherical particles, and may thus beconsidered “template-free” methods. Many previous methods utilize atemplating method that involves forming a sacrificial core, which can bepre-formed or formed in situ, that is coated with a silane. Then, afterdecomposing the core via chemical, thermal, or evaporative treatments,the core is removed and a silica shell is left behind. The material(s)used to construct such a sacrificial core is referred to as a“template”, and may include organic solid particles, inorganic solidparticles, emulsion droplets, vesicles, aggregates, and gas bubbles.Specific examples of templates include polystyrene particles,poly(vinylpyrrolidone) particles, polystyrene-containing co-polymers(e.g., PS-PVP co-polymers, PS-PVP-PEO triblock co-polymers), fattyamines (e.g., octylamine, dodecylamine), and the like, such as thosedescribed in EP1922290A2; Liu et al. “Preparation of hollow silicaspheres with different mesostructures” Journal of Non-CrystallineSolids, 2008, 354, 826-830; Deng et al. “Hollow chitosan-silicananospheres as PH-senstive targeted delivery carriers in breast cancertherapy” Biomaterials, 2011, 32, 4976-4986; Gorsd et al. “Synthesis andCharacterization of Hollow Silica Spheres”, Procedia Materials Science,2015, 8, 567-576; Yu et al. “facile Synthesis of PDMAEMA-coated hollowmesoporous silica nanoparticles and their pH responsive controlledrelease”, Microporous and Mesoporous Materials, 2013, 173, 64-69—eachincorporated herein by reference in its entirety. In preferredembodiments, a template is not employed in the disclosed method forforming the hollow silica spheres, and most preferably, the hydrolyzablearyl silane is the only organic starting material employed.

The thus synthesized hollow silica spheres may be used ‘as is’, or maybe further functionalized to suit a particular application, for example,for use in slow release or pH-responsive drug delivery applications orother carrier applications, biosensors, catalysis, cosmetics, adsorbentapplications, fillers in polymer, building, or constructionapplications, etc. Indeed, the hollow silica spheres may be surfacemodified by coating/grafting with poly(N,N-dimethylaminoethylmethacrylate) (PDMAEMA), bi-reactive silanes such as gyycidyl-contianingsilanes (e.g., (3-glycidyloxypropyl) trimethoxysilane (GTPMS)), cationicpolysaccharide-chitosan, or various other coatings known by those orordinary skill in the art.

Hollow Silica Spheres (HSS)

In some embodiments, the hollow silica spheres comprise asilica-containing shell surrounding a core, wherein thesilica-containing shell has a higher density of silica compared to thecore. The density of silica in the core and silica-containing shellportions can be determined by measuring the peak intensities of eachwith transmission electron microscopy, for example. The core may thus bedefined as the central area in which the lower silica density begins,and which the higher silica density of the surrounding structure (i.e.,the silica-containing shell) stops.

In some embodiments, the silica-containing shell comprises greater than90 wt. % SiO₂, preferably greater than 95 wt. % SiO₂, preferably greaterthan 98 wt. % SiO₂, preferably greater than 99 wt. % SiO₂, preferablythe silica-containing shell consists of or consists essentially of SiO₂.

In some embodiments, the calcining step removes most or preferably allaryl groups that originate from the hydrolyzable aryl silane, from thehollow silica spheres. FTIR can be used to determine thepresence/absence of such aryl groups in the hollow silica spheres. Asdemonstrated by FIG. 4A, the presence of aryl C—H asymmetricalstretching vibration peak at about 3100 cm⁻¹ indicates the presence ofaryl groups prior to calcination, while the absence of this peak afterthe calcining procedures described herein indicates removal of at least90%, preferably at least 95%, preferably at least 99% by weight of thearyl groups (FIG. 4B)

The shape of the core may generally determine the shape of the hollowsilica spheres. In a preferred embodiment, the hollow silica spheres arespherical or substantially spherical. Sphericity is a measure of howclosely the shape approaches that of a mathematically perfect sphere,and is defined as the ratio of the surface area of a perfect spherehaving the same volume as a hollow silica sphere to the surface area ofthe hollow silica sphere (with unity being a perfect sphere). Preferablythe hollow silica spheres have a high sphericity, with an averagesphericity of at least 0.9, preferably at least 0.92, preferably atleast 0.94, preferably at least 0.96, preferably at least 0.98,preferably at least 0.99. In some embodiments, the hollow silica spheresare classified based on roundness, and are categorized herein as beingsub-rounded, rounded, or well-rounded, preferably well-rounded, usingvisual inspection similar to characterization used in the Shepard andYoung comparison chart (FIGS. 2 and 3C).

Of course it is also envisaged that hollow silica particles may bemanufactured in shapes other than spheres having high sphericities androundness as described above. By way of example, particles may beproduced in shapes such as rods, cylinders, rectangles, triangles,pentagons, hexagons, prisms, disks, platelets, cubes, cuboids, flakes,stars, flowers, and urchins (e.g. a globular particle possessing a spikyuneven surface).

In preferred embodiments, the methods disclosed herein produce hollowsilica spheres which are uniform. As used herein, the term “uniform”refers to no more than 10%, preferably no more than 5%, preferably nomore than 4%, preferably no more than 3%, preferably no more than 2%,preferably no more than 1% of the distribution of the hollow silicaspheres having a different shape. For example, the hollow silica spheresare highly spherical (e.g., have an average sphericity of at least 0.9)and have no more than 1% of nanocomposite hollow particles in an oblongshape. Included in this definition of “uniform” is the degree in whichthe hollow silica spheres remain intact. In preferred embodiments, thesilica-containing shell completely surrounds the hollow core, so that nofluid or compound may ingress into or egress out of the core exceptthrough pores located within the silica-containing shell. However, whena sphere is ruptured slightly so that silica-containing shell does notcompletely surround the core, the ruptured sphere tends to take on anappearance of a deflated, dimpled, or crumpled sphere, and thus tends tohave a lowered sphericity (e.g., below that of 0.9). Similarly, when asignificant rupture occurs, the spherical particles may take on the formof angular shards or fragments which have a substantially differentshape than highly spherical particles. Therefore, uniformity may also beused to measure the mechanical resistance to rupture, with adequateuniformity (e.g., no more 10% of particles having a varied shape) beingan indicator for high mechanical strength of the produced hollow silicaspheres.

The “degree of hollowness” of the hollow silica spheres as used hereinis in indicator of the density differential between thesilica-containing shell and the core, with higher degrees of hollownessbeing associated with an increased capacity for storage (e.g., ofpharmaceutical or cosmetic payloads), adsorption, etc. The degree ofhollowness is defined as a maximum peak intensity of the core divided bya minimum peak intensity of the silica-containing shell, each of whichare measured by transmission electron microscopy. That is, given thehigher density of silica in the silica-containing shell than in thecore, it is more difficult for a beam of electrons to pass through thesilica-containing shell, resulting in intensity profiles that can beused to quantify this silica density disparity. For example, the dottedlines in FIGS. 3B and 3D signify the minimum peak intensity of thesilica-containing shell of a hollow silica sphere, with the apex ofintensity located in between the dotted lines signifying the maximumpeak intensity of the core. The degrees of hollowness can then becalculated for the individual hollow silica spheres and averaged. Insome embodiments, the hollow silica spheres produced herein have anaverage degree of hollowness of 3 to 8, preferably 3.2 to 7.5,preferably 3.4 to 7.0, preferably 3.6 to 6.5, preferably 3.8 to 6.0,preferably 4.0 to 5.5, preferably about 4.06. Such a degree inhollowness is much higher (i.e., more hollow) than silica spheres whichhave not been calcined, which have an average degree of hollowness ofabout 2.3. The difference in the degree of hollowness between hollowsilica spheres produced by the inventive methods disclosed herein, andthose which have been produced with the same process except without thecalcination step can be clearly seen visually in FIGS. 3C and 3A,respectively.

In some embodiments, the silica-containing shell has a thickness ofabout 150 to 210 nm, preferably 160 to 200 nm, preferably 170 to 190 nm,preferably 180 to 185 nm. In some embodiments, the core has a diameterof about 100 to 230 nm, preferably 110 to 220 nm, preferably 120 to 210nm, preferably 130 to 200 nm, preferably 140 to 190 nm, preferably 150to 180 nm, preferably 160 to 170 nm. In preferred embodiments, thesilica-containing shell is of “uniform thickness”, meaning an averageshell thickness that differs by no more than 10%, no more than 8%, nomore than 6%, no more than 4%, preferably no more than 2%, preferably nomore than 1% at any given location on the silica-containing shell.

In some embodiments, the methods herein produce hollow silica sphereswith an average diameter of 490 to 540 nm, preferably 500 to 530 nm,preferably 505 to 525, preferably 510 to 520, with the diameter beingthe longest linear distance measured from one point on the particlethough the center of the particle to a point directly across from it.Instead, when no calcination procedure is performed, the non-calcinedsilica spheres have much larger particle sizes, with an average diameterof about 760 nm.

“Dispersity” is a measure of the homogeneity/heterogeneity of sizes ofparticles in a mixture. The coefficient of variation (CV), also known asrelative standard deviation (RSD) is a standardized measure ofdispersion of a probability distribution. It is expressed as apercentage and may be defined as the ratio of the standard deviation (σ)to the mean (μ, or its absolute value |μ|), and it may be used to showthe extent of variability in relation to the mean of a population. In apreferred embodiment, the hollow silica spheres of the presentdisclosure have a narrow size dispersion, i.e., are monodisperse, with acoefficient of variation of less than 30%, preferably less than 25%,preferably less than 20%, preferably less than 15%, preferably less than12%, preferably less than 10%, preferably less than 8%, preferably lessthan 5%, preferably less than 3%, with the coefficient of variationbeing defined in this context as the ratio of the standard deviation tothe mean diameter of the hollow silica spheres.

In some embodiments, the hollow silica spheres produced by the methodsherein are in the form of distinct particles which are not present asagglomerates, meaning the hollow silica spheres are well-separated fromone another and do not form clusters (FIG. 3C). On the other hand,non-calcined silica spheres are typically interconnected formingagglomerates made of two or more spheres that share an outer silicaboundary (FIG. 3A).

The methods of the present disclosure advantageously produce hollowsilica spheres having surface characteristics and porosities that makethem suitable for use in a variety of applications, for exampledelivery, adsorption, biosensor, catalysis, and/or cosmeticapplications. Such surface characteristics (e.g., specific surface area,Langmuir surface area, t-pot external surface area, etc.) and porosities(e.g., pore diameters, pore volume, etc.) can be measured, for example,using a gas sorption instrument such as a Micrometrics ASAP 2020 plussystem (Micrometrics, USA). In some embodiments, the hollow silicaspheres are produced with a specific surface area (BET surface area ormultilayer adsorption) in the range of 350 to 450 m²/g, preferably360-440 m²/g, preferably 370-430 m²/g, preferably 380-420 m²/g,preferably 390-415 m²/g, preferably 400-410 m²/g, preferably 405-408m²/g, preferably about 406 m²/g. The specific surface area of the asproduced hollow silica spheres is greater than the specific surface areaof the non-calcined silica spheres, which is about 4-5 m²/g.

In some embodiments, the hollow silica spheres have a Langmuir surfacearea (monolayer adsorption) of 550 to 700 m²/g, preferably 560-690 m²/g,preferably 570-680 m²/g, preferably 580-670 m²/g, preferably 590-660m²/g, preferably 600-650 m²/g, preferably 610-640 m²/g, preferably about635 m²/g. The Langmuir surface area of the hollow silica spheresproduced with the inventive methods is therefore greater than theLangmuir surface area of the non-calcined silica spheres, which is about7.5-8.5 m²/g.

The t-plot method is a well-known technique which allows determining theexternal micro- and/or mesoporous volumes and the specific surface areaof a sample by comparison with a reference adsorption isotherm of anonporous material having the same surface chemistry. In someembodiments, the hollow silica spheres have a t-plot external surfacearea of 40 to 75 m²/g, preferably 45 to 70 m²/g, preferably 50 to 65m²/g, preferably 55 to 60 m²/g, preferably about 58 m²/g. On the otherhand, non-calcined silica spheres have a t-plot external surface area of5-6 m²/g.

In preferred embodiments, the hollow silica spheres of the presentdisclosure have an average pore diameter of 1.7 to 8 nm, preferably 2.0to 6 nm, preferably 2.1 to 4 nm, preferably about 2.2 nm, and a BJHadsorption cumulative pore volume (of pores between 1.7 nm and 300 nm)of 0.02 to 0.035 cm³/g, preferably 0.024 to 0.030 cm³/g, preferably0.026 to 0.028 cm³/g, or about 0.027 cm³/g. In contrast, the averagepore diameter and the BJH adsorption cumulative pore volume (of poresbetween 1.7 nm and 300 nm) for silica spheres which have not beencalcined are 10-11 nm and 0.016-0.017 cm³/g, respectively.

The methods disclosed herein also form robust hollow silica sphereshaving desirable mechanical strength that resist rupture when placedunder certain stresses, and this can be seen for example in theuniformity of the hollow silica sphere produced (FIG. 2). One way totest the mechanical strength is to subject the hollow silica spheres toultrasonication for 5-10 min at a frequency of 5-30 kHz, preferably10-25 kHz, preferably 15-20 kHz, and with a power intensity of 25-50W/cm², preferably 30-45 W/cm², preferably 35-40 W/cm² at 20-25° C. Acomparison between the number of broken/ruptured hollow silica spheresbefore and after the sonication using visual inspection, for examplewith SEM or TEM images, then provides a measure of mechanical strength,in terms of the percent remaining highly spherical (e.g., having anaverage sphericity of at least 0.9). In some embodiments, the hollowsilica spheres produced by the methods of the present disclosure remainuniform after subjecting to ultrasonication. That is, no more than 10%,preferably no more than 5%, preferably no more than 1% of thedistribution of the hollow silica spheres rupture (have a sphericity ofless than 0.9) upon prolonged exposure to ultrasonication. Thiscontrasts to most hollow silica spheres produced by template methods,which tend to crater or rupture easily under mechanical stress and thushave the tendency to be non-uniform, i.e., greater than 10% of apopulation having a different shape (Liu et al. “Preparation of hollowsilica spheres with different mesostructures” Journal of Non-CrystallineSolids, 2008, 354, 826-830; Gorsd et al. “Synthesis and Characterizationof Hollow Silica Spheres”, Procedia Materials Science, 2015, 8,567-576).

The methods disclosed herein also advantageously produce hollow silicaspheres which have at least marginal solubility in water and thus can beused more readily in aqueous-based applications, such as in vivo drugdelivery. In some embodiments, the hollow silica spheres have asolubility in water at ambient conditions of 0.1 to 50 mg per 10 mL ofwater, preferably 0.2 to 45 mg per 10 mL of water, preferably 0.5 to 40mg per 10 mL of water, preferably 1 to 35 mg per 10 mL of water,preferably 2 to 30 mg per 10 mL of water, preferably 3 to 25 mg per 10mL of water, preferably 5 to 20 mg per 10 mL of water, preferably 10 to15 mg per 10 mL of water. Conversely, silica spheres which have not beencalcined using the procedures described herein, have limited or nosolubility in water under ambient conditions (FIG. 5), with solubilitiesless than 0.1 mg per 10 mL of water, preferably less than 0.01 mg per 10mL of water, preferably less than 0.001 mg per 10 mL of water,preferably 0 mg per 10 mL of water. Such low or no aqueous solubilitymay prohibit the use of non-calcined silica spheres in certainapplications such as drug delivery without performing surfacemodification steps to aid the aqueous solubility, which of course comesat the expense of time, scalability, material throughput, and productioncost.

From the above description it is clear that the methods of the presentdisclosure, which most notably involve use of a hydrolyzable aryl silaneand a multi-stage calcining procedure, provide hollow silica sphereshaving superior uniformity, degrees of hollowness, mechanicalproperties, aqueous solubility, surface characteristics, etc. comparedto non-calcined variants. Further, the inventors have unexpectedlydiscovered that the particular multi-stage calcining proceduresdescribed herein surprisingly provides hollow silica spheres withsuperior sphericity, degree of hollowness, uniformity, and/ormonodispersity, compared to otherwise identical processes usingdifferent calcining programs, for example methods employing single-stagecalcining procedures. By way of example, when a single-stage calcinationprocedure (that is, one that involves ramping from one temperature toanother at a particular rate without any intermediate holding steps) isemployed that involves calcining the precipitate by heating up to 600°C. at a ramp rate of 10° C./min, the resulting product has a lowsphericity (e.g., less than 0.9), is not uniform (e.g. more than 10% ofthe distribution have a different shape), is not substantially hollow(e.g., has a degree of hollowness of less than 2), and has a lowmonodispersity (has a particle size coefficient of variation of greaterthan 30%), as can be seen from FIGS. 6A-6D.

This is surprising since the ramping rate and final calciningtemperature of the single-stage calcination program are similar to thoseemployed in the multi-stage calcining program of the present disclosure.Without being bound by theory, the superior and unexpected resultsdemonstrated may be because the multi-stage (e.g., two-stage)calcination program provides sufficient time for the aryl groups of thehydrolyzable aryl silane to sequester and orient themselves within thecenter of the spherical particles, while the silanol functionalityaggregate to face the surroundings, akin to the packing behavior ofoil-in-water micelles. Therefore, the step-wise temperature increase ofthe multi-stage program may advantageously allow for reorientation ofthe hydrophobic and hydrophilic groups while the aryl groups areultimately being removed through the increasing temperature, therebyforming the hollow core and providing the hollow silica spheres with theaforementioned properties without the need for templates.

The above described advantages enable the hollow silica spheres to beuseful in many applications, including drug delivery/carrierapplications, biosensors, catalysis, cosmetics, adsorbent applications,fillers in polymer, building, or construction applications, and thelike.

In particular, the aqueous solubility properties of the hollow silicaspheres allows them to be used directly as a carrier for sustainedrelease of antitumor agents. For example, the hollow silica spheres maybe loaded with one or more antitumor agents such as adriamycin, taxol,docetaxel, vincristine sulfate, fluorouracil, methotrexatum, novantrone,cyclic adenosine monophosphate, cyclophosphamide, peplomycin sulfate,nitrocaphane, solazigune, aclarubicin hydrochloride, carmustine,temozolomide, lomustine, carmofur, tegafur, dactinomycin, mitomycin,amsacrine, amifostine, cisplatin, alarelin, aminoglute-thimide,chlormethine hydrochloride, and the like, including derivatives thereof,for combating various types of cancers, including, but not limited to,lung cancer, breast cancer, melanoma, colon cancer, pancreatic cancer,glioma, hepatic tumors, pulmonary tumors, bone tumors, adrenal tumorsand other solid tumors. The mode of delivery is not limited and mayinvolve targeted or non-targeted delivery, for example throughcombination with a targeting agent such as tumor specific folic acidligand or a tumor specific antibody.

Further, due to the sphericity, degree of hollowness, high surfaceareas, and porosity, the products formed from the methods disclosedherein are result in small pressure drops, making them especiallysuitable for adsorptive applications for processing of gases, vapors,liquids and solutions. Accordingly, the hollow silica spheres are usefulfor various chromatographic applications.

Having generally described this disclosure, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified. The examples below are intended tofurther illustrate protocols for preparing and testing the hollow silicaspheres and they are not intended to limit the scope of the claims.

EXAMPLES

Hydrolysis/Condensation

Silica spheres were obtained from the following hydrolysis/condensationreaction of phenyltrimethoxysilane (PTMS) (FIG. 1), using proceduressimilar to literature reports [B. P. M. Marini, F. Pilati, and P.Fabbri, Colloids Surf., 2008, A 317, (1-3); Y. Taniguchi, K. Shirai, H.Saitoh, T. Yamauchi and N. Tsubokawa, Polymer, 2005, 46, 2541-2547; H.J. Hah, J. S. Kim, B. J. Jeon, S. M. Koo and Y. E. Lee, ChemicalCommunications, 2003, 14, 1712-1713—each incorporated herein byreference in their entirety]. In the first step, 0.96 mL ofphenyltrimethoxysilane (PTMS) was dissolved in 80 mL of 6.6 mM Nitricacid (HNO₃) and stirred and isothermal water bath at (60° C.). Thehydrolysis develops rapidly at the adjacency of the PTMS/water interfacewithin 3 minutes of the initial acidic condition. This is followed bythe addition of 13.6 mL of ammonium hydroxide (NH₄OH) solution (33%)initiated the condensation reaction. The clear mixture solutionimmediately became a milky solution. The precipitated particles wereremoved from the condensed solution via centrifugation and then theywere washed first with ethanol and then water, respectively. Finally,they were dried at 70° C.

Calcination Procedure to Form HSS

0.1 grams of the above synthesized precipitate based on PTMS was heatedin a furnace by the following temperature program: temperature wasscanned by 5° C./min up to 200° C. and then it was kept at the sametemperature for 30 minutes. Finally, the temperature was increased by1.5° C./min to 660° C. and held for 16 hours to form the hollow silicaspheres.

Morphological Characterization

The morphological features of the prepared silica particles wereexamined using scanning electron microscopy (SEM) and transmissionelectron microscopy (TEM). FIG. 2 shows the SEM micrograph of thecalcinated specimen prepared through the above method with PTMS. Thesilica particles were monodisperse and displayed the spherical shapewith a smooth and uniform texture. The average size of the spheres wasestimated around 515±15 nm, consistent in size and shapes. The spheresdisplayed the hollow morphology as judged by the contrasts of the coreand shell of the spheres.

The as prepared silica spheres (before and after calcination) werefurther analyzed by TEM. FIG. 3A shows a TEM micrograph of HSS beforecalcination. The morphology of the spheres is consistent with themorphology observed by SEM. However, the size of the spheres seems to bebigger than the size of the spheres after the calcination (FIG. 3A vs.FIG. 3C). This observation was confirmed when the average size of theuncalcinated spheres was measured (˜760 nm). FIG. 3C shows the purehollow silica spheres after the calcination program (finishing at 660°C.). The spheres appeared smaller in size when they were compared withthe uncalcinated spheres, the average size (510 nm) is consistent withSEM measurements. Furthermore, a noticeable contrast between the coreand the shell of the spheres was observed in the TEM images, which wasmore obvious for the calcinated spheres compared to the non-calcinedspheres. The cores appeared brighter than the shells indicating thehollow nature of the core. The less dense/hollow regions scatter fewerelectrons compared to denser parts and appeared brighter in contrast.The hollow nature of the spheres was further clarified by extracting theintensity profiles of the spheres (FIGS. 3B and 3D). This profile showsa peak in the intensity (increased intensity) in each core of thespheres which is due to the hollow nature of the core. On the otherhand, the shells showed a significant decline in the intensity profiledue to the solid nature compared to the core of the spheres. Theseobservations are consistent with the conclusions made by SEM (FIG. 2)that the silica particles prepared were of hollow structure. Also, fewfractured spheres were seen in these images.

Chemical Analysis and Thermal Stability

The major chemical bonds of the silica and thermal stability of theproduct were confirmed by Fourier transform spectroscopy (FTIR) andthermal gravimetric analysis (TGA), respectively. Prior to calcination,FIG. 4A shows a strong absorption peak at 1130 cm⁻¹ that can beattributed to Si—O—Si asymmetric stretching. The peaks located at 728and 489 cm¹ are due to symmetric stretching vibration of Si—O units, andthe absorption at 968 cm¹ is due to bending of Si—OH. A weak distinctiveSi—OH stretching vibration was displayed at about 3600 cm¹. The peak at3100 cm¹ belongs to asymmetrical stretching vibration of CH groups ofaromatic phenyl attached to HSS. These results demonstrated condensationproduct of PTMS to form HSS.

After calcination the strong peak at 1081 cm¹ belongs to Si—O—Siasymmetric stretching (see FIG. 4B). The peaks at 797 and 444 cm¹ aredue to the symmetric stretching vibration of Si—O groups. Clearly, allthe phenyl groups were removed and the samples include only silicamatrix in HSS.

TGA plots show the thermograms of calcinated and non-calcinated HSS. Thehollow silica spheres (HSS) before calcination were stable only under600° C. while the HSS were much more stable after calcination (FIG. 4C).HSS with calcination: no weight loss. Slight weight loss at low T<100°C. is humidty. HSS without calcination: weight loss at around 500° C. isdue to loss of phenyl groups. It is clear by FIG. 4C that the samplewithout calcination exhibited a single step degradation starting at 400°C., corresponding to a loss of phenyl groups which is about 20% of thetotal weight. The calcinated sample shows no weight change up to 900° C.

Solubility

When a soluble test was conducted for both calcinated and non-calcinatedproducts, only the calcinated spheres were soluble in water.Uncalcinates were hydrophobic in nature due to the presence of phenylgroups and float on the surface of the water (FIG. 5), consistent withprevious reports [H. J. Hah, J. S. Kim, B. J. Jeon, S. M. Koo and Y. E.Lee, Chemical Communications, 2003, 14, 1712-1713—incorporated herein byreference in its entirety]. The calcinated product was soluble in water,a property achieved for the first time, which may open many researchopportunities for bio-medical applications.

Surface Area Analysis

Surface area analysis was conducted on a micrometrics ASAP 2020 plusinstrument using the following parameters:

-   -   Non-calcined product—0.1219 g sample mass, 49.6289 cm³ cold free        space, N₂ analysis adsorptive, −195.725° C. analysis bath        temperature, 17.0334 cm³ measured warm free space, 10 s        equilibration interval, using nitrogen on silica-alumina        reference material;    -   Calcined product—0.1109 g sample mass, 48.3405 cm³ cold free        space, N₂ analysis adsorptive, −195.734° C. analysis bath        temperature, 16.5409 cm³ measured warm free space, 10 s        equilibration interval, using nitrogen on silica-alumina        reference material.

BET analysis is readily used to precisely measure the specific surfacearea (A_(SS)) of the porous materials. In this study, the BET analysiswas performed to measure the A_(SS) of calcined and un-calcined hollowsilica spheres (HSS). The uncalcined product showed A_(SS) value around4.8 while calcined HSS around 406.4 m²/g. The measured A_(SS) ofcalcined HSS is around 100 times higher than HSS before calcination(Table 1). The Langmuir Surface Area was found around 8 and 635 m²/g fornon-calcined and calcined products, respectively. The non-calcinatedsample adsorption average pore diameter (4V/A by BET): 10.1790 nm andthat of calcinated one is 2.2396 nm. These data are in agreement withTEM results where the size decreased from ˜700 nm to 500 nm due toshrinkage upon calcination.

TABLE 1 BET surface Area data for calcined and non-calcined HSS SpecificLangmuir t-Plot Surface Surface external Pore Area Area surface areavolume* A_(ss) A_(Ls) A_(es) BJH Sample (m²/g) (m²/g) (m²/g) (cm³/g)Non-calcined 4.7865 7.9261 5.5845 0.016025 HSS Calcined HSS 406.4764635.34 58.4453 0.027569 *Cumulative pore volume based on pores having awidth between 1.7-300 nm

Comparative Example

Precipitates were prepared by the hydrolysis/condensation reactions asdescribed above and then subjected to the following single-stagecalcination procedure: heated up to 600° C. with a heating rate of 10°C./min. FIGS. 6A-6D shows a sampling of the product produced. As can beseen from these figures, the products formed are of varying sizes (notmonodisperse) and shapes with low sphericity (angular) and no hollowstructure.

Thus, the foregoing discussion discloses and describes merely exemplaryembodiments of the present disclosure. As will be understood by thoseskilled in the art, the present disclosure may be embodied in otherspecific forms without departing from the spirit or essentialcharacteristics thereof. Accordingly, the disclosure of the presentinvention is intended to be illustrative, but not limiting of the scopeof the disclosure, as well as other claims. The disclosure, includingany readily discernible variants of the teachings herein, defines, inpart, the scope of the foregoing claim terminology such that noinventive subject matter is dedicated to the public.

The invention claimed is:
 1. A method for forming hollow silica spheres,the method comprising: dissolving a hydrolyzable aryl silane in anaqueous solution comprising water and an acid to form a hydrolyzedsilane solution; mixing the hydrolyzed silane solution with a hydroxidebase to form a precipitate; and calcining the precipitate to form thehollow silica spheres, wherein the calcining is performed by heating toa first temperature of 180 to 240° C. with a first ramp rate of 3 to 10°C./min and holding the first temperature for 2 minutes to 2 hours, thenheating to a second temperature of 600 to 740° C. at a second ramp rateof 0.1 to 4° C./min, and holding the second temperature for 2 to 24hours, wherein a template is not employed for forming the hollow silicaspheres.
 2. The method of claim 1, wherein the hydrolyzable aryl silaneis a trialkoxyarylsilane.
 3. The method of claim 1, wherein thehydrolyzable aryl silane is trimethoxyphenylsilane.
 4. The method ofclaim 1, wherein the acid is nitric acid.
 5. The method of claim 1,wherein the hydroxide base is ammonium hydroxide.
 6. The method of claim1, wherein the first temperature is 195 to 210° C.
 7. The method ofclaim 1, wherein the first ramp rate is 4 to 6° C./min.
 8. The method ofclaim 1, wherein the first temperature is held for 15 to 45 minutes. 9.The method of claim 1, wherein the second temperature is 650 to 670° C.10. The method of claim 1, wherein the second ramp rate is of 1 to 2°C./min.
 11. The method of claim 1, wherein the second temperature isheld for 12 to 20 hours.
 12. The method of claim 1, wherein the hollowsilica spheres comprise a silica-containing shell surrounding a core,wherein the silica-containing shell has a higher density of silicacompared to the core.
 13. The method of claim 12, wherein the hollowsilica spheres have an average degree of hollowness, defined as amaximum peak intensity of the core divided by a minimum peak intensityof the silica-containing shell, each measured with transmission electronmicroscopy, of 3 to
 8. 14. The method of claim 12, wherein thesilica-containing shell has a thickness of about 150 to 210 nm, and thecore has a diameter of about 100 to 230 nm.
 15. The method of claim 1,wherein the hollow silica spheres have an average diameter of 500 to 530nm.
 16. The method of claim 15, wherein the hollow silica spheres aremonodisperse with a coefficient of variation, defined as a ratio of thestandard deviation to the mean diameter of the hollow silica spheres, ofless than 5%.
 17. The method of claim 1, wherein the hollow silicaspheres have a solubility in water of 0.1 to 50 mg per 10 mL of water.18. The method of claim 1, wherein the hollow silica spheres have aspecific surface area of 350 to 450 m²/g.
 19. The method of claim 1,wherein the hollow silica spheres have an average pore diameter of 1.7to 8 nm with a cumulative pore volume of 0.02 to 0.035 cm³/g.